rs2915959

Positions:

chr19-38506969-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000540.3(RYR1):c.8816+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,611,250 control chromosomes in the GnomAD database, including 67,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8622 hom., cov: 31)

Exomes 𝑓: 0.28 ( 58616 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -3.46

Variant links:

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 19-38506969-T-A is Benign according to our data. Variant chr19-38506969-T-A is described in ClinVar as [Benign]. Clinvar id is 93303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38506969-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.8816+17T>A		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.8816+17T>A	intron_variant	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.8816+17T>A	intron_variant	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.2268+17T>A	intron_variant, NMD_transcript_variant	1		ENSP00000470927
RYR1	ENST00000599547.6 linkuse as main transcript	c.8816+17T>A	intron_variant, NMD_transcript_variant	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49396

AN:

151504

Hom.:

8586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.431

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.336

GnomAD3 exomes

AF:

0.320

AC:

80107

AN:

250066

Hom.:

13753

AF XY:

0.320

AC XY:

43326

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.437

Gnomad AMR exome

AF:

0.391

Gnomad ASJ exome

AF:

0.242

Gnomad EAS exome

AF:

0.339

Gnomad SAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.295

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.275

AC:

402080

AN:

1459630

Hom.:

58616

Cov.:

AF XY:

0.280

AC XY:

203207

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.433

Gnomad4 AMR exome

AF:

0.387

Gnomad4 ASJ exome

AF:

0.252

Gnomad4 EAS exome

AF:

0.338

Gnomad4 SAS exome

AF:

0.444

Gnomad4 FIN exome

AF:

0.293

Gnomad4 NFE exome

AF:

0.250

Gnomad4 OTH exome

AF:

0.293

GnomAD4 genome

AF:

0.326

AC:

49493

AN:

151620

Hom.:

8622

Cov.:

AF XY:

0.334

AC XY:

24698

AN XY:

74042

show subpopulations

Gnomad4 AFR

AF:

0.432

Gnomad4 AMR

AF:

0.356

Gnomad4 ASJ

AF:

0.258

Gnomad4 EAS

AF:

0.360

Gnomad4 SAS

AF:

0.459

Gnomad4 FIN

AF:

0.290

Gnomad4 NFE

AF:

0.253

Gnomad4 OTH

AF:

0.341

Alfa

AF:

0.276

Hom.:

1128

Bravo

AF:

0.333

Asia WGS

AF:

0.484

AC:

1682

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Central core myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

RYR1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

King Denborough syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.074

DANN

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over